Clinical and translational aspects of malignant progression and pancreatic cancer

Abstract

Pancreatic cancer (PDAC) has poor prognosis with limited effects of treatment. The progression model of PDAC from mutations to premalignant lesions takes years to evolve, with a window of intervention if we only knew how and what to target to stall malignant progression. Accumulation of p62 is implicated in PDAC carcinogenesis. Chemoresistance in PDAC contributes to short survival and is poorly understood. Neoadjuvant FOLFIRINOX is under evaluation and has shown conflicting results. The overall aim was to explore aspects of malignant progression to PDAC and to investigate effects of neoadjuvant FOLFIRINOX in patients with resected PDAC. Paper I investigated expression of proteins by IHC in resected tumors from PDAC patients. In paper II, a retrospective crossover study was performed. The adjunct of cyst fluid mucin biomarker panels (MUCPs) was evaluated in a clinical setting. In paper III, IHC was performed on tumor tissue from patients with PanIN, IPMN and PDAC. This paper also included tumor tissue samples from KRASG12D mice, an animal model of progression of PDAC. Protein expression related to autophagy, ROS and NFκB pathway was analysed. In paper IV, the effect of neoadjuvant FOLFIRINOX versus upfront surgery on gene expression in resected PDAC tumor samples was assessed using single-cell RNA-seq (scRNA-seq). In Paper I, high expression of p62 was associated with shorter disease-free survival, 7 versus 29 months (p=0.017). The hazard ratio for death was 2.88 in patients with high p62. Paper II revealed that the adjunct of MUCPs in a clinical setting, identified and improved correct decision of surgery in 2/88 patients with pancreatic lesions. In Paper III, expression of p62 was significantly higher in patients with PDAC than in PanINs and IPMN lesions and CD45 was significantly higher in PDAC than in PanINs. In mouse KRASG12D tumor samples, there was significant different expression of p62 between lesion types that followed a U-shaped pattern which was also noticed for the expression of NFκB. Paper IV showed modest differences in gene expression in tumors from patients treated with neoadjuvant FOLFIRINOX versus upfront surgery. However, these differences are consistent with increased chemoresistance, stress adaptation and cancer cell survival. In conclusion high expression of p62 was associated with poor survival. The adjunct of MUCPs can ameliorate correct surgical decision-making of high-risk pancreatic lesions in single cases. High p62 and associated NFκB pathway activation are early events in malignant progression. Neoadjuvant FOLFIRINOX shows no major effects on gene expression compared with upfront surgery in scRNA-seq analysis. The minor differences seen, support selective pressure towards chemoresistance and cancer survival